Neurodegenerative diseases are one of the major threats to human health. Their common pathological features are abnormal entanglement of proteins and their amyloidosis in nerve cells, and associated neuronal apoptosis and neurological impairment. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most typical two of them. The clinical manifestations of AD are characterized by memory and cognitive dysfunction and changes in personality and behaviors, while the clinical manifestations of PD mainly include static tremor, bradykinesia, muscular rigidity, postural gait disorder and other dyskinesia. Both AD and PD mainly occur among old people, and the incidence increases with age. Taking AD for example, the incidence among the people above 65 is 5%, but above 30% among the people above 80. Therefore, the number of patients, suffering from these two diseases, is increasing incessantly as the prolonging of lifespans and the intensifying of population aging. AD, in particular, by far has affected more than 40 million patients, which would reach 150 million in 2050. For the United States alone, more than 200 billion U.S. dollars are spent on AD patients caring per year, as twice as cancer, which makes it the most expensive disease of the world. The number of PD patients of the world, according to a conservative estimation, has exceeded 10 million. However, the etiology of these two diseases is still unknown. In terms of clinical treatment, although several drugs have been approved by the US FDA to treat mild and moderate AD or PD, these drugs are neurotransmitter regulating drugs that can only temporarily improve the patient's cognitive or motor functions. The symptoms will rebound soon as soon as ceasing the drugs. Till now, no drug can terminate or reverse the pathological process of these two diseases. Therefore, it is extremely meaningful to develop new drugs for the treatment of AD or PD.
The research finds that: The amyloid proteins in the brains of AD patients are mainly β-amyloid (Aβ) protein and Tau protein, as well as a small amount of α-synuclein (α-syn), and the initial site of onset is the hippocampus that performs the functions of memory and learning and spatial orientation in the brain. The brain damage of PD patients starts from the substantia nigra, which is responsible for somatic motor function. The difference in the initial site of onset determines different symptoms of the patients with these two diseases. However, studies indicate that more than half of AD patients have dyskinesia in the later stage, and most PD patients also share the same symptoms of AD patients in the later stage. These phenomenons suggest that the two diseases have intrinsic correlations in pathogenesis and disease progression.
The formation of senile plaques in the brain is one of the basic pathological features of AD. As a main constituent substance in the senile plaques, Aβ is a polypeptide consisting of 36-43 amino acids, which is a hydrolysis product of amyloid precursor protein (APP), wherein the content of Aβ(1-40) accounts for more than 90% of the total amount of Aβ. The current study has clarified that although Aβ has normal physiological functions and can regulate acetylcholinergic signaling between synapses by regulating the catalytic activity of cholinesterase, but excessive aggregation and fibrosis of Aβ in the brain can cause synapse dysfunction, and subsequent secondary inflammatory response, leading to loss of neuronal function and neuron death. Therefore, developing substances that can inhibit the aggregation and fibrosis of Aβ as well as block its neurotoxicity is one of the important approaches for the research and development of AD medication.
The pathological features of PD are mainly manifested as progressive loss of dopamine (DA)-ergic neurons in the nigrostriatal system, along with the production of Lewy bodies. The Lewy bodies mainly comprise hollow radial amyloid fibers formed by the aggregation of denatured α-syn. α-Syn is located at the presynaptic membrane terminal of neurons, and the natural state in the body is a soluble and unfolded state. Misfolding of α-Syn occurs under pathological conditions, generates β-sheet structures, which in turn are aggregated and fibrillated to form Lewy body lesions. Research indicates that amyloidosis of α-syn plays a key role in the pathological process of the disease. Therefore, inhibiting α-syn aggregation and fibrosis has become one of the approaches in the research and development of medication for PD's prevention and treatment. On the other hand, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin. It is not toxic per se, but after it enters the brain, 1-methyl-4-phenylpyridine cation (MPP+) generated from its metabolism can destroy DA-ergic neurons in the substantia nigra. At the same time, MPP+ can also interfere with NADH dehydrogenase, an important substance in the respiratory chain of mitochondrial metabolism, then causes cell death and accumulation of free radicals. The mass death of DA-ergic neurons caused by this process severely affects the cerebral cortex's motion control, resulting in similar symptoms of PD. Therefore, MPTP and MPP+ are widely used in the establishment of PD-related animal models and cell models as well as the research and development of PD medications.
Gold nanoparticles are nanoscale gold particles (the diameter of the gold cores of the gold nanoparticles used in research is greater than 3 nm in general). Because of the unique optical and electric properties, good biocompatibility as well as convenient surface modification, gold nanoparticles are widely used in biology and related medical fields such as biosensors, medical imaging and tumor detection. Due to the chemical inertness and large specific surface area and the ability to penetrate the blood-brain barrier at low concentrations, gold nanoparticles are also used as drug carriers in the research of directional transport and controllable release of drugs, etc. In the recent years, research is made on binding gold nanoparticles with specific ligands (such as heteropolyacids and specific sequence polypeptides) that inhibit the aggregation of fibrotic proteins, achieving certain effects in vitro protein fibrosis inhibition experiments. (Y. H. Liao, Y. J. Chang, Y. Yoshiike, Y. C. Chang, Y. R. Chen, Small 2012, 8, 3631; Y. D. Alvarez, J. A. Fauerbach, J. V. Pellegrotti, T. M. Jovin, E. A. Jares-Erijman, F. D. Stefani, Nano Letters 2013, 13, 6156; S. Hsieh, C. W. Chang, H. H. Chou, Colloids and Surfaces B: Biointerfaces, 2013, 112, 525), but the results of the cell model indicate that although there is a synergistic effect on cell viability when gold nanoparticles (gold core size is above 5 nm) are used together with compounds that have a protective effect on fibrin damaged cells (N. Gao, H. Sun, K. Dong, J. Ren, X. Qu, Chemistry-A European Journal 2015, 21, 829), the effect is not obvious when they are used alone. AD experiments at the level of animal model have not yet been reported. Moreover, in these researches, gold nanoparticles were mainly used as drug carriers other than as active ingredients.
Gold clusters (AuCs) are ultrafine gold nanoparticles with a gold core less than 3 nm in diameter. It contains only a few to hundreds of gold atoms, causing the face-centered cubic packing structure of the gold atoms in the conventional gold nanoparticles to collapse and the energy level to split, thus showing molecule-like properties that are completely different from the conventional gold nanoparticles of above 3 nm: On the one hand, due to energy level splitting, AuCs do not possess the surface plasmon effect and derived optical properties of conventional gold nanoparticles, but exhibit excellent fluorescence emission properties similar to semiconductor quantum dots. On the other hand, in the ultraviolet-visible absorption spectrum of AuCs, the plasmon resonance peak at 520±20 nm disappears, while one or more new absorption peaks appear above 560 nm, and such absorption peaks cannot be observed in conventional gold nanoparticles. Therefore, the disappearance of the plasmon resonance absorption peak (520±20 nm) and the appearance of the new absorption peaks above 560 nm in the UV-visible absorption spectrum are important indicators for judging whether AuCs are successfully prepared (H. F. Qian, M. Z. Zhu, Z. K. Wu, R. C. Jin, Accounts of Chemical Research 2012, 45, 1470). AuCs also have magnetic, electrical and catalytic properties and photothermal effects that are significantly different from those of conventional gold nanoparticles, so they have broad application prospects in the fields of single-molecule optoelectronics, molecular catalysis, and photothermal conversion.
In addition, AuCs have also been used in the fields of bioprobes and medical imaging due to their excellent fluorescence emission properties. For example, Sandeep Verma team uses purine-modified AuCs as green fluorescent probes for nucleus imaging, (J. R. Wallbank, D. Ghazaryan, A. Misra, Y. Cao, J. S. Tu, B. A. Piot, M. Potemski, S. Wiedmann, U. Zeitler, T. L. M. Lane, S. V. Morozov, M. T. Greenaway, L. Evaes, A. K. Geim, V. I. Falko, K S. Novoselov, A. Mishchenko, ACS Applied Materials & Interfaces 2014, 6, 2185). This type of literatures utilizes the fluorescence properties of AuCs and does not involve the medicinal activity of AuCs themselves.